Preparation comprising glycol solutions of alkali metal salts of barbituric acid compounds



Patented Dec. 18, 1934 Q I I UNITED STATES PATENT OFFICE PREPARATION COMPRISING GLYCOL SOLU- I TIONS OF ALKALI METAL SALTS- F BARBI'I'URIC ACID COMPOUNDS John W. Forbing, Albany, N. "Y", assignor to .Winthrop Chemical Company, Inc., New York,

N. Y., a corporation of New York No Drawing. Application April 29, 1931, Serial No. 533,868-

8 Claims. (Cl. 16752) The object of my invention is the production of drogen atoms by two hydroxyl groups, for ina stable and sterilizable solution of an alkali metal stance, ethylene glycol HO.CH:.CH:.OH, propylene salt of a compound of the barbituric acid series to glycol CHa.CH( OH) .CH2.OH, trimethylene glycol be used for medicinal purposes. More particu- HO.CH2.CH2.CH2.OH, the four butylene glycols,

o larly my invention relates to substantially anetc. As is known, the glycols dissolve readily in lwdrous preparations comprising solutions of an water. They are soluble in the cellular lipoids and alkali metal salt of a compound of the barbituric are apparently of little effect and relatively acid-series in a glycol. physiologically inactive when injected into the The compounds of the barbituric acid series, tissue. Iprefer to use ethylene glycol or propylene 10 particularly those which contain aryl, alkyl, alglycol for the purpose set forth; l0

kylene, alkylidene, cyclohexenyl and the like resi- The process of preparing my new stable soludues are of great importance in medicinal therapy. tions may be carried out by dissolving the dry Of particular importance are, for example, dialkali metal salt of the barbituric acid compound ethyl-barbituric acid, dipropyl-barbituric acid, in a glycol, preferably in ethylene glycol, in the d fly -beb u e acid. ph yl-ethyl-barbituric absence of water,or by dissolving the free bar- 15 acid, cyclohexenyl-ethyl-barbituric acid etc. and bituric acid compound inthe glycol in which the substitution Dredllcts Of these o pounds. calculated amount of alkali metal has been dis- T tu c acids themselves are not ufl solved under anhydrous conditions, and therei nt y s u l in water and in the humors of the upon sterilizing the solution obtained, if desired.

tissues and in the serum of the animal body. It The sterilization may be effected by heating, 20 has been, therefore, necessary to P p solutions which is not injurious to the solutions, or by addof the alkali metal salts of the barbituric acids ing suitab1e germicides, Suppositories may bein water for injections. The alkali metal salts prepared from t glycol solutions, while of the barbituric acids. however, are rather un- (finding t by means of uitame vehicles, such stable in the presence of water and depending on as i m teal-ate, 5 tim and t mp atu act rs, th y u d The glycols have roved to possess in a satismi l d mp s t p o a l y yd l sis. factory'degree the property of dissolving the al- Whieh a is n r m' decided disadvantage in kali metal salts of the therapeutically valuable the use of the said substances for m dicin l pure barbituric acids even in the absence of water. It

.10 poses and often renders the preparations even y he noted, however, t t t alkah t l useless and h r p y inactive salts of the various barbituric acids are not all For these reasons u u solutions of the alkali soluble to the same degree in the above specified metal salts of the barbituric acids must be freshly Solvents and t t th r may even be such salts p p before use and cannot sml'ed and as are not sufliciently soluble in glycols to be .xnarketedm a manner necessary to guarantee used for medicinal purposes. Therefore, I wish 35 therapeutlc rehablhtyit to be understood that I do not claim solutions Ihave found that y dissolvmsthe alkahmetal of such barbituric acid alkali metal salts the salts of barbituric acids in glycols in the absence Solubility of which in substantially anhydrgus Otwa stable Sterilizable sohitions are glycols might be sufficiently negligible so as to ren- 40 2335i???s'gg figggggg g ggafi g g fi; der such solutions therapeutically inapplicable.

, It may be pointed out that it is very essential rFctal My new s: gi 'i z s to avoid any substantial amount of water in the Q 2 225 2 22 gg gs gz' g i as glycol solutions. Glycols containing a relatively ampules, etc. or, it intended for rectal use, in the large pelicentaige of Wat? may perhaps have" a form of suppositories. The fact that the solutions higher dISSQIVmF cafpamty for the alkali metal are Stable and do not lose their activity by the salts of barbituric ac1ds,but suchwater-containing decomposition or dissociation of the alkali metal solutmns are much 185.5 stabte than the substansalts, permits the storing and marketing of the tiauy anhydmus Solutlons smce the water present causes a considerable decrease of the stabilpreparations in ready-made doses convenient for dispensing and speedy admimstration ity of such solutions, probably due to dissociation The solvents used for preparing my stable soluof the salts. v

tions are the dihydric alcohols or glycols, i. e. the The following examples serve to illustrate my compounds which may be regarded as derived invention, but the invention is not limited to these from the parafiins by the replacement of two hyexamples. 5%

1. 324 grams oi dried sodium-phenyl-ethylbarbituric acid are placed into a suitable container, and 725 cc. 01 pure ethylene glycol are added. The mixture is then agitated while protecting it against the moisture of the air and, if desired, heated until solution is complete. The solution is then cooled and diluted with a further quantity of the solvent to the desired concentration, for instance, to such volume that one cubic centimeter will contain about 5 grains of sodiumphenyl-ethyl-barbituric acid. The solution may be filtered before or after diluting. The solution may be made sterile by addition of germicides or by heating before, or after, filling it into suitable containers, such as ampules, etc.

The glycol solution can also be prepared in the following manner:

29.3 grams of metallic sodium are dissolved in 725 cc. of pure ethylene glycol, and 295.5 grams of phenyl-ethyl-barbituric acid are added while protecting the mixture against the moisture of the air. When solution is complete it may be diluted, if desired, with a further quantity of the solvent so that, for instance, 1 cc. thereof contains about 5 grains of phenyl-ethyl-barbituric acid.

2. 110 grams of dried sodium-diethyl-barbi-' turic acid are introduced into a suitable container, and 800 cc.- of pure ethylene-glycol are added. The salt is dissolved in the solvent, as indicated in Example 1, and the solution is made up, by further addition of the solvent, to such volume that one cubic centimeter contains about 1.7 grains of the above specified sodium" salt.

3. 324 grams of dried sodlum-cyclohexenyl ethyl-barbituric acid are placed into a suitable container, and 725 cc. of pure ethylene glycol are added. The salt is dissolved as stated in Example 1, and the solution is diluted to the desired con-' centration by adding a further quantity of the solvent. For example, a solution may be prepared, each cubic centimeter of which contains about 5 grains of the above specified sodium salt.

4. 324 grams of dried sodium-diallyl-barbituric acid are dissolved in pure ethylene glycol and made up, if desired, to a volume of 1000 cc. by adding the requisite quantity of ethylene glycol.

5. 324 grams of dried sodium-phenyl-ethylbarbituric acid are dissolved in pure propylene glycol and made up to the desired concentration, torinstance, to a volume of 1000 00., by adding the necessary amount of the solvent.

6. 25.3 grams of sodium-phenyI-ethyl-barbi-.

turic acid are dissolved in 37.5 grams of ethylene glycol while heating. v

3.5 grams of sodium stearate, or a sufllcient quantity of the sodium salt of another suitable fatty acid or a mixture of such salts, are dissolved in '15 grams of ethylene glycol .while heating. The two solutions are mixed and strained, or filtered, while still hot and liquid. The liquid mixture is poured into molds of the desired'volume,

for instance of such volume that on cooling the finished suppository will contain about 5 grains of the sodium salt of phenyl-ethyl barbituric acid.

7. 8.3 grams of the sodium salt of diallyl-barbituric acid are dissolved in 13.3 grams oi. ethylene glycol while heating.

A solution of 0.33 grams of stearic acid and 2.46 grams of sodium stearate in 24.1 grams of ethylene glycol is prepared by heating to about 100 C., and thetwo solutions are mixed, strained, or filtered, while hot and poured into suitable molds, for instance of such a volume that on cooling the finished suppository will contain about 5 grains of the sodium salt of diallyl-barbituric acid.

I claim:

1. As new compositions of matter, stable and sterilizable, substantially anhydrous preparations for medicinal purposes consisting of a substantially anhydrous glycol and dissolved therein an alkali metal salt of a compound of the barbituric acid series.

2. As new compositions of matter, stable and sterilizable, substantially anhydrous preparabituric acid.

5. As a new composition of matter, a stable and sterilizable, substantially anhydrous preparation for medicinal purposes consisting of substantially anhydrous ethylene glycol having in solution therein the sodium salt of diallyl-barbituric acid.

6. As a new composition of matter, a stable and sterilizable, substantially anhydrous prepa ration for medicinal purposes consisting of substantially anhydrous ethylene glycol having in solution therein the sodium salt of phenyl-ethylbarbituric acid in a quantity corresponding to about 5 grains of phenyl-ethyl-barbituric acid in each cubic centimeter of ethylene glycol.

7. As new compositions of matter, stable and sterilizable, substantially anhydrous preparations for medicinal purposes consisting of substantially anhydrous propylene glycol and dissolved therein an alkali metal salt of a compound of the barbituric acid series.

-8. As new compositions of matter, stable and sterilizable, substantially anhydrous prepara tions for medicinal purposes consisting of substantially anhydrous propylene glycol and the sodium salt of phenyl-ethyl-barbituric acid.

- JOHN .w. FORBING. 

